Process for the preparation of hydrocortisone

ABSTRACT

A compound of the formula ##STR1## wherein K is a protective group of the oxo of the formula ##STR2## wherein n is 2 or 3 and L is a 11β-hydroxy, the dotted line in the 11-position is not a bond and X is chlorine, bromine or iodine which avoids an 11-hydroxylation step in the preparation of hydrocortisone.

PRIOR APPLICATION

This application is a division of U.S. patent application Ser. No.362,120 filed Dec. 22, 1994 now U.S. Pat. No. 5,502,182, which is adivision of U.S. patent application Ser. No. 105,742 filed Aug. 12,1993, now U.S. Pat. No. 5,401,840 which is a division of U.S. patentapplication Ser. No. 935,535 filed Aug. 25, 1992, now U.S. Pat. No.5,260,463.

STATE OF THE ART

European patent No. 30,368 describes a process for the preparation ofhydrocortisone which has the problems of low yield and by productformation.

OBJECTS OF THE INVENTION

It is an object of the invention to provide an improved process for thepreparation of hydrocortisone and to provide novel intermediatestherefor.

This and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel process of the invention for the preparation of hydrocortisonehaving the formula ##STR3## comprises subjecting a halohydrin of theformula ##STR4## wherein X is chlorine, bromine or iodine to arearrangement reaction in the presence of an alcohol to obtain aftertreatment with an acid a compound of the formula ##STR5## selectivelyprotecting the 3-oxo function by the action of a thiol or a dithiol ofthe formula

    HO--(CH.sub.2).sub.n --SH or HS--(CH.sub.2).sub.n --SH

in which n is equal to 2 or 3 to obtain a compound of the formula##STR6## wherein K is a protective group of the 3-oxo of the formula##STR7## in which n is defined as previously, or a compound of formulaII as defined above is treated with a selective blocking agent of the3-oxo function as defined above to obtain a compound of the formula##STR8## wherein X and K are defined as above, subjecting the latter toa rearrangement reaction in the presence of an alcohol to obtain, aftertreatment with an acid, a compound of formula IV as defined abovereacting said compound of formula IV with a trihaloacetate of theformula

    Hal.sub.3 C--CO.sub.2 R

wherein Hal is chlorine or bromine and R is alkyl of 1 to 6 carbon atomsor aralkyl of 7 to 15 carbon atoms or a silyl residue in the presence ofzinc and a Lewis acid to obtain a compound of the formula ##STR9##wherein K, Hal and R are as defined above, reacting the latter in abasic medium with a phenol of the formula ##STR10## wherein R_(a) andR_(b) are individually selected from the group consisting of hydrogen,hydroxy, alkyl and alkoxy of 1 to 4 carbon atoms to obtain a compound ofthe formula ##STR11## wherein K, R, R_(a) and R_(b) are defined asabove, reacting the latter with a reducing agent to obtain a compound ofthe formula ##STR12## wherein K, R_(a) and R_(b) are defined as above,deprotecting the 3-oxo function to obtain a compound of the formula##STR13## wherein R_(a) and R_(b) are defined as above, reacting thelatter with an epoxidation agent to obtain a compound of the formula##STR14## wherein R_(a) and R_(b) are defined as above and hydrolyzingthe latter in an acid medium to obtain a compound of formula I.

In a modification of the process of the invention, the halohydrin of theformula ##STR15## wherein X is defined as above is subjected to arearrangement reaction in the presence of an alcohol to obtain, aftertreatment with an acid, the compound of the formula ##STR16## the 3-oxofunction or the latter is selectively protected by the action of a thiolor a dithiol of the formula

    HO--(CH.sub.2).sub.n --SH or HS--(CH.sub.2).sub.n --SH

wherein n is defined as above to obtain a compound of the formula##STR17## wherein K is defined above, the latter is reacted with areagent of the formula Hal₃ C--CO₂ R wherein Hal and R are defined asabove and then the synthesis is continued as described previously.

In another variation of the process of the invention, a compound offormula II as defined above is reacted with a selective protection agentof the 3-oxo as defined above to obtain a compound of the formula##STR18## wherein X and K are defined as above, subjecting the latter toa rearrangement reaction in the presence of an alcohol to obtain, aftertreatment with an acid, a compound of formula IV as defined above, thensaid compound of formula IV is treated with a reagent of the formula

    Hal.sub.3 C--CO.sub.2 R

in which Hal and R are defined as above, and then the synthesis iscontinued as described above.

When R is alkyl, it is preferbly methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl or hexyl. When R is aralkyl, it isperferably benzyl or phenethyl. When R is silyl remainder, it is, forexample, a trialkylsilyl remainder such as trimethylsilyl, tert-butyldimethylsilyl, or also, triphenylsilyl or diphenyl tert-butylsilylremainder.

When R_(a) and R_(b) are alkyl, they are selected preferably from ethyl,linear or branched propyl, linear or branched butyl or, preferably,methyl. When R_(a) and R_(b) are alkoxy, they may be ethoxy, linear orbranched propoxy, linear or branched butoxy or, preferably, methoxy. Inthe compound of formula II, X is preferably bromine.

The rearrangement reaction of the halohydrin is preferably carried outin the presence of a higher alcohol or a polyalcohol, for exampleglycerol or a diol such as propylene glycol or, preferably ethyleneglycol, used in excess, by heating to a temperature lower than 100° C.It may be advantageous to operate in the presence of a cosolvent,preferably with a boiling point lower than 100° C., at reflux of thiscosolvent The cosolvent is an inert solvent under the reactionconditions, for example, ethyl acetate.

The acid treatment is carried out by an aqueous acid, for example,hydrochloric acid, hydrobromic acid or sulfuric acid. The protection ofthe 3-oxo function is carried out by the action of a dithiol in an acidmedium, notably ethanedithiol in the presence of concentratedhydrochloric acid or hydrobromic acid, in a catalytic quantity, or inthe presence of a Lewis acid such as zinc chloride, titaniumtetrachloride or boron trifluoride, preferably in the form of theetherate.

Preferably the blocking of the 3-oxo function is carried out, and thenthe rearrangement of the halohydrin is carried out according to aso-called "one pot" method, that is to say without isolating theintermediate of formula V. The rearrangement of the halohydrin isfacilitated by the intermediate blocking of the 3- or 3,17 oxo functionswhich allows the use of very gentle operating conditions.

It can be indicated, for information only, that the consequence ofblocking appears to be the labilization of the carbon-halogen bond inposition 9 which therefore facilitates the rearrangement.

The Lewis acid used in the reaction of the compound of formula IV withthe trihaloacetate is, for example, zinc chloride, aluminium chloride,diethylaluminium chloride, or, preferably, titanium tetrachloride. Inparticular, an alkyl trihaloacetate is used and quite particularlymethyl or ethyl trichloroacetate. The operation preferably takes placein a cyclic ether such as tetrahydrofuran or dioxane.

The action of the phenol on the compound of formula VI is carried out inthe presence of a base which can be, for example, an alkali metal oralkaline-earth metal hydroxide or carbonate, particularly sodium,potassium, barium or calcium, a hydride, an alcoholate or an alkalimetal amide, particularly sodium, potassium or lithium or an alkyllithium, particularly butyl lithium. The operation takes place in anorganic solvent such as a ketone like acetone or methylethyl ketone, ifappropriate in a mixture with a halogenated solvent such as methylenechloride or with an ether such as dioxane or tetrahydrofuran.

Preferably in the process as defined above, the phenol is of the formula##STR19## wherein R_(a) and R_(b) are hydrogen, hydroxy or methyl.

The reducing agent can be a metal hydride, preferably aluminium, forexample the double lithium aluminium hydride of diethyl sodium aluminiumhydride, diisobutyl aluminium hydride or also sodium dihydrobis(2-methoxyethoxy) aluminate. The operation takes place preferably intoluene or tetrahydrofuran. The reducing agent can also be an alkalimetal borohydride, for example, sodium borohydride, catalyzed, ifappropriate, by a lithium salt, or lithium borohydride.

The deprotection of the 3-oxo function is carried out by the action ofiodine in the presence of a base such as an alkali metal bicarbonate, orby the action of iodine in a catalytic quantity in the presence of anoxidizing agent, preferably hydrogen peroxide, by the action of methyliodide, glyoxylic acid, or also metal salts such as mercury or cadmium.Generally the operation takes place in a solvent such as a loweralkanol, for example, methanol or ethanol, in admixture with ahalogenated solvent, for example, methylene chloride, in the presence ofwater.

The epoxidation agent can be a peracid such as meta-chloroperbenzoicacid, perphthalic acid, pertungstic acid or hydrogen peroxide used aloneor in the presence of hexachloro- or hexa-fluoroacetone. The epoxidationagent can also be a hydroperoxide such as tert-butyl hydroperoxide usedin the presence of the vanadium acetyl acetonate or other metals such asmolybdenum in a catalytic quantity. The operation takes place in anorganic solvent such as methylene chloride, carbon tetrachloride,chloroform, methanol, tetrahydrofuran, dioxane, toluene or ethylacetate, if appropriate in the presence of water and can also take placein a buffered medium, for example, disodium phosphate or a trisodiumphosphate-phosphoric acid mixture.

The hydrolysis of the epoxide in the 17,20-position is carried out bythe action of an aqueous acid, the acid being, particularly a mineralacid such as hydrochloric acid, sulfuric acid or nitric acid can alsotake place in a buffered medium, such as those mentioned above.

The new synthesis of hydrocortisone of the invention presents a certainnumber of advantages, which are summarized as follows: The rearrangementleading from the 11-OH compound to the 11-keto compound via theintermediate halohydrin, is carried out under far more gentle conditionsthat those described in the European Patent No. 30,368, which presentsan advantage both in the level of the reaction yield because theformation of secondary or degradation products is limited, and anadvantage on the industrial level to the extent that the synthesis ismore economical; The blocking in position 3 is remarkably selective incontrast to the known blockings by enol ethers and ketals which lead tomixtures of products blocked in positions 3 and 3,17; The blocking inthe 3-position in the invention is very stable under the reactionconditions used whether they are acidic or basic, and its eliminationduring synthesis, notably by the action of iodine in a basic medium oriodine in catalytic quantity under gentle oxidizing medium, is veryeasy; Access to hydrocortisone is possible without going through ahydroxylation stage in the 11-position which is the case with knownsynthesis using androstenedione at the start. Accordingly, this improvesthe overall yield of the process.

Among the novel intermediates of the invention are the compounds of theformula ##STR20## wherein K is a protective group of the oxo of theformula ##STR21## or preferably ##STR22## wherein n is 2 or 3 andparticularly 2, and either L is oxo and the dotted line in the11-position is a bond and X is hydrogen, or L is 11-hydroxy, the dottedline in 11-position is not a bond and X is chlorine, bromine or iodineand particularly bromine, the compounds of the formula ##STR23## whereinK is a protective group of the oxo of the formula ##STR24## orpreferably ##STR25## wherein n is 2 or 3 and particularly 2 and M iseither chlorine or bromine and preferably chlorine or ##STR26## whereinR_(a) and R_(b) have the meaning above and are preferably hydrogen,hydroxy or methyl and R has the meaning above and preferably is methylor ethyl as well as the compounds of the formula ##STR27## whereineither K' is oxygen or K, which is a protective group of the oxo of theformula ##STR28## or preferably ##STR29## wherein n is 2 or 3 andpreferably is 2, the dotted line in the 17-position is a bond, R_(a) andR_(b) have the above meaning and preferably are hydrogen, hydroxy ormethyl, or K' is oxygen, the dotted line in 17-position is epoxy andR_(a) and R_(b) have the meaning above.

The compounds of formula II are described in particularly in U.S. Pat.No. 3,072,684.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 1

Preparation of hydrocortisone

STEP A: Cyclic 3-[(1,2-ethanediyl)-mercaptole of Δ⁴-androstene-3,11,17-trione

a) Δ⁴ -Androstene-3,11,17-trione.

1.05 g of 9 α-bromo-Δ⁴ -androstene-11β-ol-3,17-dione, 7.5 ml of ethylacetate and 2.5 ml of ethylene glycol were mixed together at ambienttemperature under an inert gas atmosphere. The mixture was refluxed withstirring for 10 hours, cooled and then 10 ml of 2N hydrochloric acid and10 ml of water were added. The mixture was stirred for 20 hours, andthen the ethyl acetate was eliminated under reduced pressure. Aftersalting out with sodium chloride and cooling to 0° C., the crystals wereseparated, washed with water and dried. The crystals were taken up inmethylene chloride, and after ethyl acetate was added, the methylenechloride was evaporated off. The solution was chilled and the crystalswere separated, then dried to obtain 0.52 g of the expected productmelting at 221° C. By extracting the aqueous phase with methylenechloride and chromatographing the crude product on silica, eluting witha methylene chloride-ethyl acetate (95-5) mixture, 0.097 g of theexpected product were obtained, which after crystallization from ethylacetate, melted at 220° C.

b) Cyclic 3-[(1,2-ethanediyl)-mercaptole] of Δ⁴-androstene-3,11,17-trione

100 ml of methanol, 5 g of the product of Step A), 1.8 ml of ethanedithiol and 2.5 ml of boron trifluoride etherate were mixed together atambient temperature under an inert gas atmosphere. After 90 minutes ofstirring, the methanol was evaporated off. The residue was taken up inmethylene chloride, washed with a saturated aqueous solution of sodiumbicarbonate, with water, dried, then brought to dryness. The productobtained was crystallized from hexane to obtain 5.99 g of the expectedproduct melting at 160° C.

NMR Spectrum (CDCl₃ 90 MHZ ppm). 18--CH₃ : 0.85; 19--CH₃ : 1.27;thioketal: 3.17 to 3.47; H₄ : 5.6

IR spectrum (CHCl₃)

Absence of Δ⁴ 3-one; absorptions at 1645 cm⁻¹ (C═C), 1709 cm⁻¹ (C=0 in11-position), 1740 cm⁻¹ (C=0 in 17-position).

STEP A': Cyclic 3-[(1,2-ethanediyl)-mercaptole] of Δ⁴-androstene-3,11,17-trione.

4 g of 9 α-bromo-Δ⁴ -androstene-11 β-ol-3,20-dione and 40 ml of ethylacetate were mixed together under an inert gas atmosphere and then 0.9ml of ethane dithiol were added at ambient temperature. Then 0.09 ml of22° Be hydrochloric acid were added slowly and the mixture was stirredfor 6 hours. Then 9.3 ml of ethylene glycol were introduced and themixture was refluxed for 20 hours, then cooled to 20° C. The reactionmixture was poured into a mixture of 40 ml of 2N hydrochloric acid and40 ml of water and after stirring for 16 hours, the ethyl acetate waseliminated under reduced pressure (20 mm/Hg) at 35° C. maximum. Thesuspension was then cooled to 0°, +5° C., stirred for 1 hour and thecrystals were separated out. The crystals were washed with water, thendried and chromatographed on silica eluting with a hexane-dioxane (9-1)mixture to obtain 3.2 g of the expected product.

NMR Spectrum (CDCl₃ 300 MHz ppm): 18--CH₃ : 0.84 (s); 19--CH₃ : 1.26(s); thioketal: 3.15 to 3.4; H₄ : 5.57; skeleton: 1.1 to 2.61 (m)

IR Spectrum (CHCl₃)

Absorptions at 1741-1709 cm⁻¹ (ketches); 1641 cm⁻¹ (C═C)

STEP B: Methyl 20-chloro-3,3-[1,2-ethanediyl-bis(thio)]-Δ⁴,17 (20)-pregnadien-11-one-21-oate

100 ml of tetrahydrofuran and 12.55 g of zinc powder were mixed togetherunder an inert atmosphere and 7.9 ml of titanium tetrachloride, then amixture of 100 ml of tetrahydrofuran, 8.6 ml of methyl trichloroacetateand 18 g of the product of Step A or A' were added slowly at -10°/-15°C. The temperature was allowed to return to ambient and then the mixturewas stirred at ambient temperature for 90 minutes. Then, 100 ml of awater--pyridine (4-1) mixture was added at +10°/+15° C. and the mixturewas stirred for 1 hour while allowing the temperature to rise. Then, 100ml of a water--concentrated hydrochloric acid (6-4) mixture was addedand the mixture was stirred for 15 minutes, followed by extraction withmethylene chloride. The organic phase was washed with water, dried andthe solvent was evaporated. The crystals were dissolved in methylenechloride and after isopropyl ether was added, the methylene chloride wasevaporated, followed by cooling. The crystals were separated out and themother liquors were chromatographed on silica eluting with acyclohexane--ethyl acetate (8-2) mixture to obtain 21.8 g of theexpected product melting at 175° C.

IR Spectrum (CHCl₃)

Absorptions at 1715 cm⁻¹ and 1730 cm⁻¹ (C=0) max. 1705 cm⁻¹ 1643 cm⁻¹(C═C Δ⁴) and 1610 cm⁻¹ (C═C)

NMR Spectrum (CDCl₃ 90 MHz ppm)

Mixture of isomers 20 C1 18--CH₃ : 1.02-0.98; 19--CH₃ : 1.25; thioketal:3.33; CH₃ -ester: 3.83-3.82; H₄ : 5.58.

STEP C: Methyl 20-phenox-3,3-[(1,2-ethanediyl-bis(thio)]Δ⁴,17 (20)-pregnadien-11-one-21-oate

A mixture of 18 g of phenol, 150 ml of butanone, 30 g of the product ofStep B and 17.7 g of potassium carbonate was refluxed under an inertatmosphere. After 16 hours, the mixture was poured into a mixture of 100ml of water, 90 g of ice and 10 ml of 10N sodium hydroxide. Extractiontook place with methylene chloride and the organic phase was washed withwater and concentrated. After taking up the residue in methanol andallowing the solution to cool slowly, the crystals were separated anddried to obtain 27.4 g of the expected product melting at 208° to 210°C.

IR Spectrum (CHCl₃)

Absorption at 1592-1491 cm⁻¹ (Aromatic C₆ H₅ -O-type); 1714-1705 cm⁻¹(C=0); 1646 cm⁻¹ (C═C)

NMR Spectrum (CDCl₃ 90 MHz ppm). 18--CH₃ : 0.9; 19--CH₃ : 1.21;thioketal: 3.33; CH₃ ester: 3.63; H₄ : 5.58; C₆ H₅ : 6.81 to 7.39Mixture of isomers 20-0--C₆ H₅

STEP D: Cyclic (11β)-3,3-[(1,2-ethanediyl)-mercaptole] of20phenoxy-Δ⁴,17 (20 )-pregnadien-11,21-diol-3-one

20 g of the product of Step C and 200 ml of toluene were mixed togetherunder an inert gas atmosphere and after cooling to -25° C., 110 ml of a20% solution of diisobutyl aluminium hydride in toluene were introducedslowly. The temperature was allowed to rise to 10° C. and the mixturewas stirred for 1 hour. Then, the mixture was cooled to -15° C. and 10ml of methanol were added slowly. The temperature was allowed to rise to0° C. and 200 ml of 2N hydrochloric acid were added slowly. Afterdecanting, the organic phase was washed with water, dried and thesolvent was evaporated. The residue was chromatographed on silicaeluting with a toluene--ethyl acetate (9-1) mixture to obtain 17.4 g ofthe expected product.

IR Spectrum (CHCl₃)

Absorption at 1490-1596 cm⁻¹ (C₆ H₅ --O--C); 1644 cm⁻¹ (C═C) .sup.Δ4)and 1682 cm⁻¹ (C═C); 3612 cm⁻¹ (free OH)

NMR Spectrum (CDCl₃ --C₅ D₅ N) (90 MHz ppm) 18--CH₃ : 1.17; 19--CH₃ :1.29; thioketal: 3.33; CH₂ OH: 4.15; H₁₁ : 4.32; H₄ : 5.45 were addedand then 0.3 g of iodine. A pH of 1.5 ml was obtained and 1.4 ml of 50%hydrogen peroxide were introduced over 15 minutes. The oxidizing powerwas neutralized by the addition of 2 g of sodium thiosulfate and then 5g of clarcel were added, followed by filtering and concentrating todryness under reduced pressure. The dry extract was dissolved inmethylene chloride, washed with a solution of 1 g of sodium thiosulfatein 25 ml of water, decanted, dried and concentrated to dryness underreduced pressure to obtain 4.8 g of the crude expected product. 1.8 g ofthis product was purified by chromatographing on silica (eluant:methylene chloride--isopropanol (97.5-2,5)) to obtain 1.7 g of thedesired product melting at 188° C.

IR Spectrum (CHCl₃)

Absorptions at 3613 cm⁻¹ (OH); 1662, 1617 and 868 cm⁻¹ (Δ⁴ -3-oxo);1597-1491 cm⁻¹ (--O--C₆ H₅)

NMR Spectrum (CDCl₃ --C₅ D₅ N--90 MHz ppm) 18--CH₃ : 1.17; 19--CH₃ Z:1.42; H₁₁ : 4.27; H₄ : 5.67; CH₂ OH: 4.11; C₆ H₅ : 6.87 to 7.37

STEP F: 17,20-epoxy-20-phenoxy-Δ⁴ -pregnadien-11β,21-diol-3-one

1.0 g of the product of Step E, 10 ml of ethyl acetate and 5 ml of waterwere mixed together under an inert gas atmosphere and 0.5 g of disodiumphosphate, 0.65 g perphthalic acid and 0.75 ml of 50% hydrogen peroxidewere added to the mixture. The mixture was stirred for 3 hours 15minutes and after another 0.15 g of disodium phosphate and 0.20 g ofperphthalic acid were added. The mixture was stirred for 75 minutes.Then 20 ml of ethyl acetate and 9 ml of 1N sodium hydroxide were addedand the mixture was stirred for 5 minutes, followed by decanting. Theorganic phase was washed with water and with a water solution of sodiumbisulfate and 1N sulfuric acid, dried and evaporated to dryness toobtain 1.05 g of the crude and unstable expected product which was usedas is for the following step. Rf: 0.28 (silica--CH₂ Cl₂ /Dioxane-90/10).

IR Spectrum (CHCl₃)

Absorption at 3613 cm⁻¹ (OH); 1662 and 1616 cm⁻¹ (Δ⁴ -3-one); 1600, 1590and 1494 cm⁻¹ (aromatic)

NMR Spectrum (CDCl₃ 300 MHz ppm)

18--CH₃ : 1.29 (s); 19--CH₃ : 1.43 (s); --C--CH₂ --O--: 3.49 (dd) and4.20 (dd); H₁₁ eq.: 4.32; H₄ : 5.68; H of O--C₆ H₅ : para 7.06 (t),ortho 7.13 (d) and meta 7.29 (t).

STEP G: Hydrocortisone

5 ml of methanol, 3 ml of water and 0.08 ml of 1N sulfuric acid (pH 2)were mixed together under an inert gas atmosphere and after 0.525 g ofthe product of Step F were added at ambient temperature, the mixture wasstirred for 16 hours. The mixture was neutralized by the addition ofsodium bicarbonate and extraction was carried out with methylenechloride. The organic phase was dried and evaporated to dryness. Theresidue was taken up in hot methylene chloride with 5% methanol, thenconcentrated until the start of crystallization. After cooling, thecrystals were separated and dried. The mother liquors were concentratedand the residue was chromatographed on silica eluting with a methylenechloride-methanol (95-5) mixture to obtain in total 0.318 g of theexpected hydrocortisone melting at 224° C. and having a specificrotation of [α]_(D) ²⁰ =+164°±2°5 (C=1% in ethanol).

IR Spectrum (nujol)

Absorption at 3430 cm⁻¹ (OH), 1710 cm⁻¹ (C=0), 1642, 1630 and 1610 cm⁻¹(Δ⁴ -3-one).

Various modifications of the process of the invention may be madewithout departing from the spirit or scope thereof and it should beunderstood that the invention is intended to be limited only as definedin the appended claims.

What we claim is:
 1. A compound of the formula ##STR30## wherein K is aprotective group of the oxo of the formula ##STR31## wherein n is 2 or 3and L is a 11β-hydroxy, the dotted line in the 11-position is not a bondand X is chlorine, bromine or iodine.